tbuckley/cabot-search huggingface dataset:
Abstract 2025: Phosphoproteomic profiling following MAP3K1 kinase inhibition identifies NPM1 as a novel substrate
Authors: Lidia Boghean, Sarbjit Singh, Kiran Mangalaparthi, Surendra K. Shukla, Smitha Kizhake, Amritha Kizhake, Donn Wishka, Jayapal Reddy Mallareddy, Joel Morris, Paul Grothaus, Pankaj K. Singh, Akhilesh Pandey, Amarnath Natarajan
Journal: Cancer Research (2023)

Abstract In response to diverse cellular cues, MAP3K1, a mitogen-activated protein kinase, participates in various cancer signaling networks including the NFκB, JNK, ERK, and p38 pathways. Functioning as a signaling kinase in these oncogenic pathways, MAP3K1 contributes to tumor growth and metastasis, thus making it an attractive therapeutic target for cancer. Structure-guided design using MAP3K1 AlphaFold and Schrödinger GLIDE led to the development of 51-106, a selective MAP3K1 small molecule inhibitor. Profiling using the KiNativTM platform in a cellular matrix revealed 51-106 as a selective ATP-competitive MAP3K1 inhibitor. 51-106 blocked TNFα-induced MAP3K1-IKKβ-mediated NFκB activity. Phosphoproteomics analysis following MAP3K1 inhibition by 51-106 showed a dose dependent decrease in NPM1 T199 phosphorylation indicating NPM1 as a novel substrate of MAP3K1. NPM1 plays a critical role in DNA damage repair; consistently we observed a dose dependent S-phase arrest upon MAP3K1 inhibition by 51-106, suggesting a dysfunctional DNA damage response. Higher MAP3K1 transcript level in pancreatic cancer patients is associated with poorer (50% vs. 15%) 5-year survival. Treatment of pancreatic cancer cell lines with the MAP3K1 inhibitor 51-106 inhibited cell growth and migration. In combination studies, 51-106 synergistically inhibited growth with gemcitabine in LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre (KPC) cell lines in vitro and in KPC syngeneic orthotopic implantation mouse model of pancreatic cancer in vivo. Our study is the first to identify NPM1 as a potential substrate of MAP3K1, and these results warrant the investigation of MAP3K1 inhibition as a therapeutic option in cancer. Citation Format: Lidia Boghean, Sarbjit Singh, Kiran Mangalaparthi, Surendra K. Shukla, Smitha Kizhake, Amritha Kizhake, Donn Wishka, Jayapal Reddy Mallareddy, Joel Morris, Paul Grothaus, Pankaj K. Singh, Akhilesh Pandey, Amarnath Natarajan. Phosphoproteomic profiling following MAP3K1 kinase inhibition identifies NPM1 as a novel substrate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2025.
Abstract 3107: Development of novel JAK2 inhibitors and PROTACs as chemical probes for the investigation of JAK2 inhibition and degradation
Authors: Briley A. Humphrey, Bao li, Renan B. Ferreira, Sujeewa R. Ranatunga, Tegan M. Rowsell, Luxin Sun, Harshani R. Lawrence, Ernst Schonbrunn, Gary Reuther, Nicholas J. Lawrence
Journal: Cancer Research (2023)

Abstract Inhibition and, more recently, degradation of protein kinases is an important therapeutic strategy to modulate disregulated signaling pathways in the cell cycle. Janus kinase 2 (JAK2) is a protein kinase involved in the JAK/STAT pathway which is one of the 12 core cancer pathways; thus, the regulation of JAK2 is important in the maintenance of normal cell function. A fragment-based drug discovery approach was taken to synthesize novel JAK2 inhibitors based using building blocks suitable for PROTAC development. Small molecule inhibitors were analyzed through computational analysis to probe the binding interactions in the hinge region of the ATP active site of JAK2. PROTACs were designed to investigate the degradation of JAK2 based on small molecule ligands with high binding affinity to JAK2. Pyrrolopyrimidine and pyrimidine scaffolds were used to probe the hydrogen bonding interactions in the hinge region to investigate binding affinity. Modification of A-ring and B-ring fragments of the inhibitors and PROTACs were used to develop SAR through data obtained by functional assays, including differential scanning fluorimetry and 33P HotSpot™ kinase assay, in addition to in-vivo cell viability assays as models for myeloproliferative neoplasms. Several key pyrrolopyrimidine and pyrimidine core containing inhibitors and PROTACs bind strongly to JAK2 and modulate JAK2 activity in appropriate cancer cell lines. Citation Format: Briley A. Humphrey, Bao li, Renan B. Ferreira, Sujeewa R. Ranatunga, Tegan M. Rowsell, Luxin Sun, Harshani R. Lawrence, Ernst Schonbrunn, Gary Reuther, Nicholas J. Lawrence. Development of novel JAK2 inhibitors and PROTACs as chemical probes for the investigation of JAK2 inhibition and degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3107.
Abstract 106: Intratumoral heterogeneity of glioblastoma is attributed to precancerous cells derived from neural stem cells
Authors: Jeong Ho Lee, Hyun Jung Kim, Seok-Gu Kang
Journal: Cancer Research (2023)

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain cancer in adults. We and other groups have identified mutation-harboring neural stem cells (NSCs) in the subventricular zone (SVZ) as cells-of-origin carrying driver mutations (Lee et al, Nature 2018). However, little is known about the evolutional process by which mutation-harboring NSCs in the SVZ transform into distant cancer cells with a high degree of molecular heterogeneity. Here, using a spontaneous, somatic mouse model that recapitulates human GBM arising from NSCs that carry driver mutations, we show that mutation-harboring NSCs transform into precancerous cells through oligodendrocyte progenitor cell (OPC) lineage specification during tumor evolution. These precancerous cells show dysregulated translation and/or modification of extracellular matrix (ECM) prior to tumor formation. They subsequently give rise to GBMs with intratumoral heterogeneity exhibiting multiple developmental cell states as in human GBM, and also show activation of additional transcriptional programs, including immune evasion, ECM remodeling, epithelial-mesenchymal transition, and proliferation. Importantly, we further identified precancerous cell populations carrying driver mutations, namely gain of chromosome 7 and loss of chromosome 10 in tumor-free SVZ tissues from GBM patients with intratumoral heterogeneity. These human precancerous cells indeed exhibited OPC and neural progenitor cell-like expression patterns similar to those in our spontaneous GBM mouse model. Thus, our results demonstrate that cell-type specification of precancerous cells with oncogenic transcriptional programs underlie evolution of GBM from mutation-harboring NSCs and intratumoral heterogeneity. Citation Format: Jeong Ho Lee, Hyun Jung Kim, Seok-Gu Kang. Intratumoral heterogeneity of glioblastoma is attributed to precancerous cells derived from neural stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 106.
Abstract 628: Liver macrophages promote breast cancer liver metastasis through migrating neutrophils and initiating NETosis
Authors: Heliang Li, Linbin Yang, Erwei Song
Journal: Cancer Research (2023)

Abstract Neutrophils extracellular traps (NETs), which are DNA scaffolds in complex with granule proteins, could be detected in the pre-metastatic liver niches and were associated with a poor survival in breast cancer patients. However, the mechanisms of neutrophils infiltration and NETs formation in the pre-metastatic liver tissues remain poorly understood. Here, we dynamically characterized the liver micro-environment of normal and 4T1-bearing BALB/C mouse models with or without liver metastasis by the single cell RNA sequencing. Interestingly, we found that CXCL1 and CXCL2, derived from the liver macrophages, were dramatically elevated in pre-metastatic livers and induced the infiltration of peripheral neutrophils by CXCR2. Besides, liver macrophages were educated by cancer cells-derived cathepsin C to secrete the CXCL1 and CXCL2. Furthermore, we identified that the complement signals were over-activated in pre-metastatic livers and induced neutrophils to NETosis. Therapeutically, targeting CXCL1, CXCL2 and complement signals could inhibit the NET formation and effectively reduce breast cancer liver metastasis. Citation Format: Heliang Li, Linbin Yang, Erwei Song. Liver macrophages promote breast cancer liver metastasis through migrating neutrophils and initiating NETosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 628.
Abstract 2293: Tumor-informed fixed and patient-specific panels for minimal residual disease (MRD) detection in early-stage NSCLC:a head-to-head comparison
Authors: Pengpeng Zhang, Zetian Gong, Yue Yu, Xiaoxuan Wang, Lei Ye, Xiaoqiang Wang, Xuan Tang, Chao Zhang, Wanglong Deng, Chao Song, Qing Xu, Yansong Li, Wei Wang
Journal: Cancer Research (2023)

Abstract Introduction: Detection of minimal residual disease (MRD) by ctDNA based on tumor-informed or tumor-naive strategy could be used as an effective method to predict the relapse of NSCLC. As for tumor-informed strategy,both fixed panel and patient-specific panel are promising methods in MRD monitoring. Patient-specific panel can be used to monitor tissue specific somatic mutations individually. Besides, fixed panel can make up for the deficiency caused by organizational heterogeneity. In this study, we compared the monitoring effect of novel tumor-informed fixed and patient-specific panels. Methods: 81 patients with stage I-III resected NSCLC were analyzed, including 45 patients (55.6%) with stage I, 15 (18.5%) with stage II and 21 (25.9%) with stage III. Tumor samples were obtained at surgery. Preoperative blood samples (baseline) were analyzed by both tumor-informed fixed and patient-specific panels based on hybrid capture. Tumor-informed fixed panel was performed by using ultra-deep (60000X) next-generation sequencing with 158 gene panel spanning 118 kb of human genome. Patient-specific panel was also performed by using ultra-deep (100000X) next-generation sequencing with customized 40 single nucleotide variants identified using whole-exome sequencing. Results: Tumor-informed fixed panel monitored 212 mutations (median, 3; range, 0-7). Most of them (95.3%) were matched in the corresponding tumor tissues. For patient-specific panels, 91% of patients were customized design 40 mutations, affected by the detection of tissue somatic mutations. Based on fixed or patient-specific panel, ctDNA mutations were detected in 46.9% vs 49.4% (P=0.75) at baseline, respectively (Stage I: 35.6% vs 37.8%, P= 0.83; Stage II: 53.3% vs 60%, P=0.71; Stage III: 66.7% vs 66.7%). Conclusions: Both tumor-informed fixed and patient-specific panel NGS assay can detect the presence of ctDNA in early-stage NSCLC. However, the detection rate of preoperative ctDNA mutations was slightly higher based on patient-specific panel. Citation Format: Pengpeng Zhang, Zetian Gong, Yue Yu, Xiaoxuan Wang, Lei Ye, Xiaoqiang Wang, Xuan Tang, Chao Zhang, Wanglong Deng, Chao Song, Qing Xu, Yansong Li, Wei Wang. Tumor-informed fixed and patient-specific panels for minimal residual disease (MRD) detection in early-stage NSCLC:a head-to-head comparison [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2293.
Abstract 5298: Multiplex immunoassay characterization of 48 cytokines, chemokines, and growth factors in colorectal cancer
Authors: Wen-Rong Lie, Harold Steiner, Sasha Williams, Munmun Banerjee, Anthony Saporita, Brooke Gilliam, Qiang Xiao
Journal: Cancer Research (2023)

Abstract Cytokines, chemokines, and growth factors are critical mediators of immune system function capable of signaling through autocrine, paracrine, and endocrine mechanisms. Their pleiotropic immunomodulatory properties allow these biomolecules to react to diverse stimuli and regulate the immune response. We developed a novel immunoassay, using Luminex xMAP technology, for the simultaneous measurement of 48 cytokines, chemokines, and growth factors in serum, plasma, and cell culture supernatant. Many of these proteins have been proposed as biomarkers of colorectal cancer (CRC) and as key regulators of the tumor microenvironment (TME). While this complex milieu can support antitumor immunity, CRC is frequently characterized by chronic inflammation driving disease progression, with the TME serving as a potent reservoir from which the cytokines, chemokines, and growth factors exert their influence. The MILLIPLEX Human Cytokine/Chemokine/Growth Factor Panel B (HCYTB-60K) assays were performed in 96-well plates and run on the Luminex LX200™ instrument. Data was acquired via xPONENT v. 4.3 software. Data analysis was performed for all immunoassays using the Belysa Immunoassay Curve Fitting Software. Commercially available serum samples obtained from colorectal cancer patients and healthy controls were evaluated for cytokine, chemokine, and growth factor expression. Of the 48 analytes tested, statistically significant increases in BAFF, sFas, SCF, and MPIF-1 were observed in colorectal cancer serum. In contrast, IL-20 and ENA-78 decreased relative to healthy controls. While the immunoassay was verified for measurement of serum and plasma samples, additional sample types may be of interest to cancer researchers. Therefore, we evaluated the ability of the 48-plex immunoassay to measure these biomarkers in CSF, urine, milk, tumor samples and exosomal isolates, establishing a profile for these proteins in each sample type. Altogether, this study uses a novel multiplex immunoassay to characterize the immunological profile of colorectal cancer serum, focusing on 48 cytokines, chemokines, and growth factors. Additionally, alternative sample types were evaluated to establish the utility of this technology for applications beyond serum, plasma, and cell culture supernatant. Citation Format: Wen-Rong Lie, Harold Steiner, Sasha Williams, Munmun Banerjee, Anthony Saporita, Brooke Gilliam, Qiang Xiao. Multiplex immunoassay characterization of 48 cytokines, chemokines, and growth factors in colorectal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5298.
Abstract 3634: Overexpression of PLK1 activates IL4/JAK/STAT6 signaling in prostatic tumor-microenvironment
Authors: Ruixin Wang, Xiaoqi Liu
Journal: Cancer Research (2023)

Abstract The correlation between PLK1 expressions with prostate cancer (PCa) stages was identified by analyzing the transcriptome profile of PLK1 in patients from the Cancer Genome Atlas (TCGA) database, and scoring the protein expression in a clinical tissue microarray (TMA) cohort. Integrating our prostate-specific PLK1 knock-in mouse model, we established an oncogenic role for PLK1 in PCa progression. To elucidate the underlying mechanism, we investigated the impact of PLK1 overexpression on prostatic tumor microenvironment (TME) in vivo. In addition, in vitro co-culture systems with both epithelial cells and macrophages were designed to uncover the regulatory function of PLK1 in macrophage polarization. We found that PLK1 induces phosphorylation of JAK3, activates the JAK/STAT6 pathway in cancer cells, and increases the secretion of IL4, which enables macrophage polarization towards the M2 phenotype in TME—ultimately accelerating PCa development. Finally, pharmaceutical inhibition of STAT6 signaling significantly reverses the PLK1-mediated M2 polarization and, subsequently, inhibits the progression of PCa. Our findings provide clinical and pre-clinical evidence to characterize the role of PLK1 in promoting PCa and novel insights into the regulatory mechanism of PLK1 in the TME. We also provide strong support for the clinical potential of targeting STAT6 for advanced PCa therapy. Citation Format: Ruixin Wang, Xiaoqi Liu. Overexpression of PLK1 activates IL4/JAK/STAT6 signaling in prostatic tumor-microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3634.
Abstract 1098: Combination of a DNA vaccine-induced immune checkpoint blockade and radiation therapy induces anti-tumor immunity
Authors: Keng-Hsueh Lan, Ying-Chun Sheng, Keng-Li Lan, KyungMann Kim, Sung-Hsin Kuo, Zachary Morris
Journal: Cancer Research (2023)

Abstract Background: Immune checkpoint blockade (ICB) immunotherapy improves survival for many cancer patients, but those with immunologically ‘cold’ tumors do not derive benefit. Radiation therapy (RT) has been demonstrated to augment antitumor immunity in preclinical and clinical studies and may enhance response to ICB in immunologically cold tumors. We have developed DNA-based, cost-effective, and versatile ICB immunotherapies. Here, we test the use of these alone and in combination with RT as a novel treatment approach in syngeneic murine melanoma models. Materials and methods: We constructed ICB DNA vaccines targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1), CTLA-4 Vax and PD-1 Vax, respectively. These were delivered to mice by intramuscular or intratumoral electroporation. The effects of combinations of ICB DNA vaccines and RT were monitored for generation of endogenous anti-CTLA-4 and anti-PD-1 antibodies, modification of tumor microenvironment (TME), and tumor response in mice bearing syngeneic B78 or B16 melanoma. Results: Intramuscular vaccination with CTLA-4 Vax and PD-1 Vax induced endogenous anti-CTLA-4 and anti-PD-1 antibodies, respectively, and the titers increased with additional vaccinations. Vaccination with CTLA-4 Vax and PD-1 Vax alone or in combination (Dual Vax) did not inhibit the murine B16 melanoma model; however, the combination of CTLA-4 Vax and RT (CTLA-4 Vax + RT) led to enhanced infiltration of the TME with effector T cells. Dual Vax combined with RT enabled systemic anti-tumor immunity in mice bearing two B16 melanoma tumors in which only one was radiated. With intra-tumoral route of vaccination, the Dual Vax + RT treatment induced a trend toward systemic anti-tumor response in the immunologically cold B78 tumor model. Conclusions: DNA vaccines that stimulate endogenous production of antibodies against immune checkpoints may serve as an alternative form of ICB. The combination of ICB DNA vaccine and RT enabled anti-tumor immunity and tumor response in preclinical models of melanoma. Citation Format: Keng-Hsueh Lan, Ying-Chun Sheng, Keng-Li Lan, KyungMann Kim, Sung-Hsin Kuo, Zachary Morris. Combination of a DNA vaccine-induced immune checkpoint blockade and radiation therapy induces anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1098.
Safety analysis of lurbinectedin versus topotecan in elderly patients.
Authors: Vivek Subbiah, Domenica Lorusso, Jose Manuel Manuel Trigo Perez, Alexandra Leary, Victor Moreno, Rebecca Kristeleit, Ignace Vergote, Jose Antonio Lopez-Vilariño, Cristian Marcelo Fernandez, Mariano Siguero, Carmen Maria Kahatt, Ali Hassan Zeaiter, Valentina Boni, Alejandro Navarro, Vanesa Gutierrez Calderon, Beatriz Pardo, Dominique Berton, Giovanni Scambia
Journal: Journal of Clinical Oncology (2023)

e20632 Background: Lurbinectedin is a selective inhibitor of oncogenic transcription. The US FDA granted accelerated approval for lurbinectedin as monotherapy (3.2 mg/m 2 q3wk) for relapsed small cell lung cancer (SCLC) based on a phase 2 basket trial (NCT02454972). The ATLANTIS trial (NCT02566993) investigated lurbinectedin 2.0 mg/m 2 plus doxorubicin 40.0 mg/m 2 q3wk versus topotecan or CAV in relapsed SCLC. The CORAIL trial (NCT02421588) evaluated lurbinectedin (3.2 mg/m 2 i.v. q3wk) compared to pegylated liposomal doxorubicin or topotecan in patients with platinum-resistant ovarian cancer. The elderly population is usually under-represented in clinical trials despite its interest due to the increased frailty and high comorbidity. Methods: Data from Basket and CORAIL trials were included in an integrated safety analysis to evaluate lurbinectedin safety profile at the approved regimen (3.2 mg/m 2 q3wk). This post hoc safety analysis compares the outcomes of lurbinectedin in elderly population (n = 207 patients ≥65 years old; Basket n = 113 and CORAIL n = 94) versus topotecan (n = 75 patients ≥65 years old; ATLANTIS n = 45 and CORAIL n = 30). Results: Treatment-related adverse events (AEs) and laboratory abnormalities regardless of relationship occurring in &gt; 10% of patients, were: Compared with topotecan, lurbinectedin showed lower frequency of treatment-related grade ≥3 AEs (53.1% vs. 85.3%; p &lt; 0.01) and grade ≥3 serious adverse events (SAEs) (19.8% vs. 34.7%; p = 0.01) and a trend for less AEs leading to treatment discontinuation (5.3% vs. 8.0%; p = 0.40) or deaths (1.4% vs. 5.3%; p = 0.08). Use of supportive treatments was significantly lower with lurbinectedin: G-CSF (17.9% vs. 29.3%; p &lt; 0.05), red blood cells transfusions (20.8% vs. 56.0%; p &lt; 0.01) or erythropoietin (2.4% vs. 14.7%; p &lt; 0.01). Conclusions: Lurbinectedin is well tolerated in elderly patients and has a predictable and manageable safety profile. No new safety signals were observed. With the limitations of cross-trial comparisons, lurbinectedin shows a clear advantage in terms of hematological toxicity compared with topotecan in patients ≥ 65 years old. Furthermore, fewer elderly patients treated with lurbinectedin had severe AEs, SAEs, treatment discontinuations and deaths compared to elderly patients treated with topotecan. Clinical trial information: NCT02454972 , NCT02566993 , NCT02421588 . [Table: see text]